A prospective, multicenter, observational study of ixazomib plus lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma in Japan.

Real-world studies permit inclusion of a more diverse patient population and provide more information on the effectiveness of treatments used in routine clinical practice. This prospective, multicenter, observational study investigated the effectiveness and safety of ixazomib plus lenalidomide and dexamethasone (IRd) in 295 patients with relapsed/refractory multiple myeloma (RRMM) in routine clinical practice in Japan. Patients had a median age of 74 years, 80.0% were aged ≥ 65 years, 42.0% had received ≥ 3 lines of prior treatment, and 28.5% were "frail" according to the International Myeloma Working Group frailty score. After a median follow-up of 25.0 months, median progression-free survival (PFS) was 15.3 (95% CI 12.4-19.5) months, while median overall survival was not reached. The overall response rate was 53.9%, and 31.5% of patients had a very good partial response or better. In the subgroup analysis, median PFS was better in patients with 1 versus 2 or ≥ 3 lines of prior treatment (29.0 vs 19.2 or 6.9 months) and paraprotein versus clinical relapse (16.0 vs 7.9 months), but median PFS was not notably affected by frailty score or age group. Dose adjustment was more frequent among patients aged > 75 years, especially early after IRd treatment initiation. Treatment-emergent adverse events (TEAEs) of any grade occurred in 84.4% of patients and 24.7% of patients discontinued treatment due to TEAEs; no new safety concerns were found. These findings suggest that oral IRd triplet regimen is an effective and tolerable treatment option for RRMM patients in real-world settings outside of clinical trials.ClinicalTrials.gov identifier: NCT03433001; Date of registration: 14 February 2018.

Impact of a third dose of anti-SARS-CoV-2 vaccine in hematopoietic cell transplant recipients: A Japanese multicenter observational study.

This prospective observational study aimed to assess the serological response and safety after the third booster shot of SARS-CoV-2 mRNA vaccines in 292 hematopoietic cell transplant (HCT) recipients. In our patients, mild systemic reactions were present in 10-40% and GVHD aggravation in 1.1%. Overall, clinically relevant response (>250 U/mL) was observed in 93.1% of allogeneic (allo)-HCT recipients and 70.6% of autologous (auto)-HCT recipients, respectively. Of note, detectable antibody response with any titer following the first two doses was a powerful predictor for adequate response after booster shot in both cohorts. For such patients, 98.8% of allo- and 92.3% of auto-HCT recipients obtained clinically relevant response after dose 3. In addition, continued systemic steroid and/or calcineurin inhibitors at the booster shot significantly correlated with serological response. These findings highlighted that booster vaccination efficiently improved serological response without safety concerns and thus recommended for the majority of HCT recipients.

Long-term outcomes of functional single ventricles associated with heterotaxy syndrome†.

OBJECTIVES: The goal of this study was to determine the long-term surgical outcomes of patients with functional single ventricles associated with heterotaxy syndrome, risk factors for mortality and factors associated with Fontan stage completion. METHODS: Overall, 279 patients with a functional single ventricle associated with heterotaxy syndrome who underwent an initial surgical procedure at our institute between 1978 and 2021 were grouped into 4 "eras" based on the surgical year during which the initial procedure was performed: era 1 (1978-1989, n = 71), era 2 (1990-1999, n = 98), era 3 (2000-2009, n = 64) and era 4 (2010-2021, n = 46). Neonatal surgery was more frequent in eras 3 and 4 than in eras 1 and 2. RESULTS: Overall, 228 patients had right atrial isomerism; 120 patients (43.0%) had a total anomalous pulmonary venous connection; and 58 patients (20.8%) underwent an initial procedure as neonates. Overall survival rates at 10, 20 and 30 years after the initial procedure were 47.1%, 40.6% and 36.1%, respectively. Neonatal surgery (P < 0.001), total anomalous pulmonary venous connection repair at the initial procedure (P < 0.001) and early era (P < 0.001) were identified as risk factors for mortality, with the last 2 variables being negatively associated with Fontan stage completion (P < 0.001 for both). CONCLUSIONS: Although era had a favourable effect on survival, total anomalous pulmonary venous connection with intrinsic pulmonary vein obstruction was associated with both mortality and Fontan stage completion. CLINICAL REGISTRATION NUMBER: R19092.

A case in which baricitinib was effective for both rheumatoid arthritis and essential thrombocythemia.

We experienced a case of rheumatoid arthritis and JAK2V617F mutation-positive essential thrombocythemia treated with baricitinib. The patient was a 72-year-old male. He was diagnosed with rheumatoid arthritis at a local clinic in April 2018. Methotrexate (MTX) was started and the dose was increased to 16 mg/week. In October of the same year, anaemia was observed and MTX was reduced, but anaemia progressed. Blood tests showed pancytopenia, and he was referred to Rheumatology on suspicion of drug-induced pancytopenia. Pancytopenia improved with discontinuation of MTX and administration of folic acid. His platelet count was markedly increased to 1,400,000/µl at one point, decreased to 400,000/µl, and then gradually increased to 700,000-1,000,000/µl. Despite taking an antiplatelet drug, he developed cerebral infarction in June 2019. The JAK2V617F mutation was noted, and he was diagnosed with essential thrombocythemia. Hydroxycarbamide was started, but the effect was insufficient. Baricitinib, a JAK1/2 inhibitor indicated for rheumatoid arthritis, was started in August with the expectation that it would also be effective for essential thrombocythemia. The platelet count decreased to ∼400,000-600,000 cells/µl, and a decrease in the C-reactive protein level and the improvement of arthritis were noted. We report this case because it is considered to be a valuable case, suggesting that baricitinib may be effective for essential thrombocythemia.

Comparison of long-term outcomes of atrial switch with Rastelli and physiological repair using left ventricle-to-pulmonary artery conduit for levo-transposition of the great arteries.

OBJECTIVES: The objectives of this study was to compare the long-term outcomes of anatomic repair using atrial switch with the Rastelli procedure versus physiological repair with left ventricle-to-pulmonary artery conduit for patients with levo-transposition of the great arteries, ventricular septal defect, and left ventricular outflow tract obstruction. METHODS: Of patients with levo-transposition of the great arteries who underwent biventricular repair between 1978 and 2001, 31 hospital survivors after anatomic repair of atrial switch and the Rastelli (anatomic group) and 14 hospital survivors after physiological repair with left ventricle-to-pulmonary artery conduit (physiological group) were enrolled. Survival rates, reoperation rates, and most recent conditions were compared. RESULTS: The overall survival rate at 20 years was 79.7% (95% CI, 66.4%-95.6%) in the anatomic group and 85.1% (95% CI, 68.0%-100%) in the physiological group (P = .87). The reoperation rate at 10 years was 19.8% (95% CI, 5.6%-34.0%) in the anatomic group and 52.0% (95% CI, 25.0%-79.1%) in the physiological group (P = .067). Only patients in the physiological group underwent systemic tricuspid valve replacement. The anatomic group showed a better cardiac index at catheterization (2.79 ± 0.75 L/min/m2 vs 2.30 ± 0.54 L/min/m2; P = .035), lower serum brain natriuretic peptide (73 ± 86 pg/mL vs 163 ± 171 pg/mL; P = .024), and better maximal oxygen uptake in the treadmill test (64.1 ± 16.5% vs 52.7 ± 17.8% of predicted normal; P = .036), although the period until most recent catheterization, blood inspection, and treadmill testing were earlier in the anatomic group. CONCLUSIONS: Preservation of the left ventricle as the systemic ventricle using anatomic repair contributes to better cardiopulmonary condition compared with physiological repair.

Fostamatinib for the treatment of Japanese patients with primary immune thrombocytopenia: A phase 3, placebo-controlled, double-blind, parallel-group study.

Fostamatinib, a spleen tyrosine kinase inhibitor, has been approved for the treatment of chronic primary immune thrombocytopenia (ITP) in the United States, Canada and some European countries. We conducted a phase 3, placebo-controlled, double-blind, parallel-group study to evaluate the efficacy and safety of fostamatinib in Japanese patients with primary ITP. Thirty-four patients were randomised to fostamatinib (n = 22) or placebo (n = 12) at 100-150 mg twice a day for 24 weeks. Stable responses (platelet ≥50 000/µl at ≥4 of the 6 visits from weeks 14 to 24) were observed in eight (36%) patients on fostamatinib and in none of the patients on placebo (p = 0.030). Overall responses (platelet ≥50 000/µl at ≥1 of the 6 visits from weeks 2 to 12) were seen in 10 (45%) patients on fostamatinib and in none of the patients on placebo (p = 0.006). Patients on fostamatinib required rescue medication less often and experienced fewer bleeding symptoms than patients on placebo. Adverse events observed were mild or moderate and were manageable. No new safety signals were identified in Japanese patients with ITP.

Predictors of impaired antibody response after SARS-CoV-2 mRNA vaccination in hematopoietic cell transplant recipients: A Japanese multicenter observational study.

HCT recipients reportedly have a high mortality rate after developing COVID-19. SARS-CoV-2 vaccination is generally useful to prevent COVID-19. However, its safety and efficacy among HCT recipients remain elusive. This large-scale prospective observational study including 543 HCT recipients with 37-months interval from transplant demonstrated high safety profiles of mRNA vaccine: only 0.9% of patients avoided the second dose due to adverse event or GVHD aggravation following the first dose. Regarding the efficacy, serological response with a clinically relevant titer (≥250 BAU/mL) was obtained in 397 (73.1%) patients. We classified the remaining 146 patients as impaired responders and compared the clinical and immunological parameters between two groups. In allogeneic HCT recipients, multivariable analysis revealed the risk factors for impaired serological response as follows: age (≥60, 1 points), HLA-mismatched donor (1 points), use of systemic steroids (1 points), absolute lymphocyte counts (<1000/µL, 1 points), absolute B-cell counts (<100/µL, 1 points), and serum IgG level (<500 mg/dL, 2 points). Notably, the incidence of impaired serological response increased along with the risk scores: patients with 0, 1-3, and 4-7 points were 3.9%, 21.8%, and 74.6%, respectively. In autologous HCT recipients, a shorter interval from transplant to vaccination was the only risk factor for impaired serological response. Our findings indicate that two doses of SARS-CoV-2 vaccine are safe but insufficient for a part of HCT recipients with higher risk scores. To improve this situation, we should consider additional treatment options, including booster vaccination and prophylactic neutralizing antibodies during the SARS-CoV-2 pandemic.

Tyrosine kinase inhibitors induce alternative spliced BCR-ABLIns35bp variant via inhibition of RNA polymerase II on genomic BCR-ABL.

To elucidate dynamic changes in native BCR-ABL and alternatively spliced tyrosine kinase inhibitor (TKI)-resistant but function-dead BCR-ABLIns35bp variant, following commencement or discontinuation of TKI therapy, each transcript was serially quantified in patients with chronic myeloid leukemia (CML) by deep sequencing. Because both transcripts were amplified together using conventional PCR system for measuring International Scale (IS), deep sequencing method was used for quantifying such BCR-ABL variants. At the initial diagnosis, 7 of 9 patients presented a small fraction of cells possessing BCR-ABLIns35bp , accounting for 0.8% of the total IS BCR-ABL, corresponding to actual BCR-ABLIns35bp value of 1.1539% IS. TKI rapidly decreased native BCR-ABL but not BCR-ABLIns35bp , leading to the initial increase in the proportion of BCR-ABLIns35bp . Thereafter, both native BCR-ABL and BCR-ABLIns35bp gradually decreased in the course of TKI treatment, whereas small populations positive for TKI-resistant BCR-ABLIns35bp continued fluctuating at low levels, possibly underestimating the molecular response (MR). Following TKI discontinuation, sequencing analysis of 54 patients revealed a rapid relapse, apparently derived from native BCR-ABL+ clones. However, IS fluctuating at low levels around MR4.0 marked a predominant persistence of cells expressing function-dead BCR-ABLIns35bp , suggesting that TKI resumption was unnecessary. We clarified the possible mechanism underlying mis-splicing BCR-ABLIns35bp , occurring at the particular pseudo-splice site within intron8, which can be augmented by TKI treatment through inhibition of RNA polymerase II phosphorylation. No mutations were found in spliceosomal genes. Therefore, monitoring IS functional BCR-ABL extracting BCR-ABLIns35bp would lead us to a correct evaluation of MR status, thus determining the adequate therapeutic intervention.

Effects of stem cell transplantation in patients with peripheral T-cell lymphoma not otherwise specified and angioimmunoblastic T-cell lymphoma.

The effects of stem cell transplantation (SCT) in patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) remain controversial. We analyzed the feasibility of SCT and risk factors associated with outcomes of PTCL-NOS and AITL patients to identify the potential clinical efficacy of SCT. We retrospectively analyzed the data of PTCL-NOS (n = 83) and AITL (n = 112) patients who received autologous (n = 10 and 16, respectively) or allogeneic (n = 12 and 4, respectively) SCT, or no SCT (n = 61 and 92, respectively) between 2008 and 2018. All PTCL-NOS and AITL diagnoses were reconfirmed by an experienced hematopathologist. Median age at PTCL-NOS and AITL diagnoses in the SCT group was younger than that in the no SCT group. Significant risk factors for lower overall survival were intermediate-high and high-risk international prognostic indexes in PTCL-NOS patients (P = 0.0052), and a > 2 modified prognostic index for T-cell lymphoma (P = 0.0079) and no SCT (P = 0.028) in AITL patients. Autologous or allogeneic SCT compared with no SCT in AITL patients resulted in 3-year overall survival of 68.6% and 100% vs. 57.2% (P = 0.018). Strategies should be developed to improve selection of PTCL-NOS and AITL patients suitable for SCT and/or additional novel therapies.

Phase I/II study of bortezomib, lenalidomide, and dexamethasone treatment for relapsed and refractory multiple myeloma.

Use of novel agents, including proteasome inhibitors and immunomodulatory drugs, has markedly improved outcomes in multiple myeloma (MM) patients. However, most MM patients eventually relapse and require salvage treatments. We report herein the result of a phase I/II study, performed from 2014 to 2017 to assess the feasibility and efficacy of a maximum tolerated dose (MTD) of lenalidomide (Len) combined with a fixed dose of once weekly subcutaneous (sc) 1.3 mg/m2 of bortezomib plus 20 mg of dexamethasone (scVRd regimen) in relapsed/refractory MM patients in the Japanese population. In the phase I part, dose-limiting toxicities were observed in three of six patients treated with 20 mg of Len; the MTD was accordingly defined as 15 mg in our cohort. In the phase II part, the recommended dose of the scVRD regimen showed a 71.4% best overall response rate, with a median overall survival of 14.8 months and a median progression-free survival of 8 months. Severe adverse events (≥ grade 3) were observed in ~ 15% of the patients, indicating the tolerability and efficacy of the regimen. Less prior treatment was associated with higher probability of durable response. This scVRd regimen may thus be a better fit for MM patients in early-stage relapse.

A Novel Hematopoietic Progenitor Cell Mobilization Regimen Comprising Bortezomib, G-CSF, and Preemptive Plerixafor for Multiple Myeloma.

Adequate hematopoietic progenitor cell collection is critical for autologous peripheral blood stem cell transplantation. Conventionally, patients with multiple myeloma are treated with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) or G-CSF alone to mobilize their peripheral blood stem cells. However, some patients exhibit insufficient stem cell recruitment in response to these regimens. Recently, plerixafor has been approved for coverage by insurance in Japan. Combination treatment with plerixafor and G-CSF is now a standard procedure. In addition, treatment with bortezomib and G-CSF results in efficient stem cell recruitment. On the basis of the results from mouse studies, we hypothesized that combination treatment with bortezomib ensures efficient mobilization and mediates in vivo purging of malignant cells. Therefore, we administered a regimen of bortezomib, G-CSF, and preemptive plerixafor to 10 patients with multiple myeloma, and analyzed its efficacy and safety. The median patient age was 68 years. We collected CD34-positive cells (median: 4.9×106/kg) in a single session of apheresis from all patients. We observed no obvious myeloma cell contamination in the collected product or serious toxicity during treatment and collection. After collection, we performed autologous peripheral blood stem cell transplantation and confirmed engraftment in all patients (median: day 10). We found that the regimen is safe and reliably facilitated the collection of sufficient autologous peripheral blood stem cells by apheresis from all patients in a single day. Despite the small patient group size, we conclude that the regimen is promising for safe and efficient collection of peripheral blood stem cells for autologous transplantation in patients with multiple myeloma.

Long-term results after palliative intra-cardiac repair for tetralogy of Fallot and diminutive pulmonary arteries.

BACKGROUND: In patients with tetralogy of Fallot with the diminutive pulmonary arteries, we sometimes have to give up the complete intra-cardiac repair due to insufficient growth of the pulmonary arteries. We have carried out palliative intra-cardiac repair using a fenestrated patch. METHODS: Of all 202 patients with tetralogy of Fallot in our centre since 1996, five patients (2.5%) with the diminutive pulmonary arteries underwent palliative intra-cardiac repair using a fenestrated patch. Mean operative age was 1.8 years. Previous operation was Blalock-Taussig shunt in 4. At operation, the ventricular septal defect was closed using a fenestrated patch and the right ventricular outflow tract was enlarged. Follow-up period was 9.8 ± 2.6 years. RESULTS: There were no operative and late deaths. Fenestration closed spontaneously on its own in four patients 2.7 ± 2.1 years after the intra-cardiac repair with a stable haemodynamics; however, the last patient with the smallest pulmonary artery index had supra-systemic pressure of the right ventricle post-operatively. The fenestration was emergently enlarged. Systemic arterial oxygen saturation was significantly and dramatically increased from 83.5 to 94% after the palliative intra-cardiac repair, and to 98% at the long term. A ratio of systolic pressure of the right ventricle to the left was significantly decreased to 0.76 ± 0.12 at the long term. Now all five patients were Ross classification class I. CONCLUSION: Although frequent catheter and surgical interventions were needed after the palliative intra-cardiac repair, this repair might be a choice improving quality of life with good results in patients with tetralogy of Fallot associated with the diminutive pulmonary arteries.

Risk of secondary primary malignancies in multiple myeloma patients with or without autologous stem cell transplantation.

Outcomes for patients with multiple myeloma (MM) have improved through use of novel treatments, especially lenalidomide combined with autologous stem cell transplantation. However, because of their increased life expectancy, an increased risk of secondary primary malignancies (SPMs) has been observed in MM patients, particularly after lenalidomide maintenance in both transplant-eligible (TE) and transplant-ineligible (TI) patients. To evaluate the incidence and risk factors of developing SPMs, we identified 17 TE-MM and 12 TI-MM patients with SPMs among 211 TE-MM and 280 TI-MM patients, including seven TE-MM and four TI-MM patients with hematological malignancies and ten TE-MM and eight TI-MM patients with non-hematological cancers, respectively. The median follow-up time from diagnosis was > 4 years. Multivariate analysis identified a history of high-dose cyclophosphamide use for peripheral blood stem cell harvest in TE-MM patients and > 65 years of age at diagnosis, or a history of adriamycin, lenalidomide, or thalidomide use in TI-MM patients as independent risk factors for SPMs (P < 0.001). Patients with a history of lenalidomide use had a lower risk of death among both TE-MM (P = 0.0326) and TI-MM (P < 0.001) patients. The survival benefit of receiving lenalidomide outweighed the increased risk of SPMs in both TE-and TI-MM patients.

Subacute Methotrexate Encephalopathy Mimicking Ischemic Stroke With Dynamic Changes on Magnetic Resonance Imaging.

We report a 35-year-old woman who suddenly developed left hemiparesis and dysarthria at 13days after treatment with intrathecal and intravenous methotrexate for intravascular large B cell lymphoma with possible central nervous system infiltration. Seven hours after onset, she developed further right hemiparesis and aphasia. However, the majority of neurologic symptoms disappeared spontaneously and completely by 34hours. We also recorded the dynamic progression and regression of abnormal signals in the bilateral corona radiata on diffusion-weighted imaging, in parallel with neurologic symptoms. The rapid reversal of MR abnormalities and neurologic symptoms allowed us to diagnose methotrexate encephalopathy, and exclude intravascular large B cell lymphoma recurrence and regular brain infarction. The case provides new data on the dynamic changes of abnormal signals on magnetic resonance imaging in methotrexate encephalopathy over a short recovery time.

Cardiac surgical strategy for extremely low-birthweight infants with pulmonary overcirculation.

OBJECTIVES: This study aimed to review the clinical outcomes of staged cardiac surgery in extremely low-birthweight infants with congenital heart disease and pulmonary overcirculation. METHODS: Six extremely low-birthweight infants with congenital heart disease and pulmonary overcirculation underwent staged cardiac surgery between 2005 and 2017. The median birthweight was 895 g (range 620-990 g), and the median gestational age was 28 weeks (range 23-31 weeks). Clinical outcomes were evaluated, and we focused on pulmonary haemodynamics. RESULTS: Pulmonary artery banding or bilateral pulmonary artery banding was performed as the initial palliation at a median age of 23 days with a median body weight of 880 g. Corrective surgery was performed at a median age of 187 days with a median body weight of 3.9 kg. All of the patients successfully underwent corrective surgery and survived to date. Pulmonary hypertension regressed after corrective surgery in all of the patients, except for 1 patient with severe bronchopulmonary dysplasia. CONCLUSIONS: Acceptable outcomes can be obtained by staged cardiac surgery in extremely low-birthweight infants with congenital heart disease and pulmonary overcirculation. While early pulmonary artery banding can lead to regression of pulmonary hypertension after corrective surgery, close follow-up is required.

Comparative analysis of pulmonary hypertension in patients treated with imatinib, nilotinib and dasatinib.

Pulmonary hypertension (PH) is a rare, but life-threatening, adverse event in patients treated with tyrosine kinase inhibitors (TKIs), such as dasatinib, but has not been fully evaluated in patients treated with imatinib or nilotinib. We used echocardiography to noninvasively assess the incidence of PH in 105 patients with chronic myeloid leukaemia (CML) treated with imatinib (n = 37), nilotinib (n = 30) or dasatinib (n = 38). The mean triscupid regurgitation peak gradient (TRPG), which reflects pulmonary arterial pressure, was 22·7 mmHg in the imatinib group, 23·1 mmHg in the nilotinib group and 23·4 mmHg for dasatinib group. These values were not significantly different, but higher than those (19·0 mmHg) in newly diagnosed CML patients. A TRPG > 31 mmHg, marking possible PH onset, was detected in 9 of 105 patients: one (2·7%) treated with imatinib, three (10·0%) with nilotinib and five (13·2%) with dasatinib. Only three patients complained of dyspnoea, whereas the other six were asymptomatic. In addition, there was a tendency toward correlation of TRPG value and age or TKI treatment duration. These results suggested that treatment with not only dasatinib, but also imatinib and nilotinib, can be associated with subclinical PH. Noninvasive echocardiography is useful for screening, especially in older patients with long-term TKI treatment.

UGT1A1 *6 polymorphism predicts outcome in elderly patients with relapsed or refractory diffuse large B-cell lymphoma treated with carboplatin, dexamethasone, etoposide and irinotecan.

The uridine diphosphate glucuronosyltransferase (UGT) gene 1A1*6 polymorphism, which affects irinotecan metabolism, has been associated with improved survival in lymphoma patients treated with of carboplatin, dexamethasone, etoposide and irinotecan (CDE-11). This study assessed the efficacy of CDE-11 relative to the UGT1A1*6 polymorphism in 27 elderly patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for high-dose chemotherapy plus autologous stem cell transplantation. The 2-year survival rate after initial CDE-11 treatment was significantly higher in patients with than without UGT1A1*6 (57% vs. 5%). The most common grade 4 adverse event in patients with the UGT1A1*6 genotypes was neutropenia (88.9%), but there were no gastrointestinal adverse events or treatment-related deaths. Disease progression was the most frequent cause of death. CDE-11 was well tolerated and provided clinical benefit to elderly patients with relapsed or refractory diffuse large B-cell lymphoma. The response to CDE-11 likely correlated with UGT1A1*6 polymorphisms, but further prospective studies are warranted to optimize irinotecan-based chemotherapies relative to UGT1A1 polymorphism.